The Bunyavirales order includes five genera, including Orthobunyavirus, Phlebovirus, Nairovirus, Hantavirus, and Tospovirus. The majority of viruses within this order (with the exception of Hantaviruses) are considered arthropod-borne viruses and are important causes of morbidity and mortality around the world. These viruses are associated with a range of clinical symptoms characterized by febrile illness and in the most severe cases fatal hepatitis, hemorrhagic fever, or neurological manifestations requiring intensive care have been reported.
Due to advances in genomic and virus identification approaches, novel bunyaviruses have been discovered and identified as important causes of human disease during recent years (1-3). One example is severe fever with thrombocytopenia syndrome (SFTS) virus, a new member of the order Bunyavirales, genus Phlebovirus (1, 4). The virus was first isolated in China in 2009 from patients presenting with a hemorrhagic fever illness (1, 5). The initial case fatality rate reported for SFTS was 12 to 30%, and a recent serosurvey among persons living in rural Jiangsu Province found that 3.6% of residents had neutralizing antibodies to SFTS virus (6). Evidence has also been obtained about the possibility of person-to-person transmission (7, 8). Furthermore, hemorrhagic fever cases with mortality rates as high as 50% have now been recognized in Japan and Korea, further highlighting the emerging potential of this pathogen (1, 2, 9-11). Therefore, SFTS virus is a highly pathogenic phlebovirus, and due to its recent emergence, the mechanism of disease pathogenesis is still unclear.
Like other members of the order Bunyavirales, SFTS virus possesses a negative sense tripartite genome consisting of the S, M, and L segments. The L segment encodes the viral RNA polymerase (L), the M segment encodes glycoproteins (Gn/Gc), and the S segment uses an ambisense coding strategy to encode a nonstructural protein (NSs) and a nucleocapsid protein (NP) (12). Although many bunyaviruses, including the prototype virus in the Bunyavirales order Bunyamwera virus (BUNV), also encodes the nonstructural protein NSm within the M segment, some members of the Phlebovirus genus, including SFTS and Uukuniemi viruses (UUKV) do not encode this viral protein (1, 13). The BUNV NSm is known to serve as a scaffold protein that associates to globular and tubular structures derived from the Golgi apparatus (14-16). These structures have been shown to harbor the ribonucleoprotein (RNP), a complex essential for the transcription and replication of viral RNA (14). Although SFTS virus does not encode the NSm protein, it has been recently suggested that the SFTS virus NSs may exert some of the NSm's function by serving as a scaffold protein and forming viral replication factories (17). Colocalization of the early endosomal marker Rab5 with the viral factories induced by SFTS virus NSs suggests that these structures are of endosomal origin and not derived from the Golgi apparatus (18). Additionally, the SFTS virus NSs protein has also been shown to play a role in the inhibition of host innate immunity (18, 19). Although these findings are consistent with previous studies on bunyavirus NSs proteins describing the NSs as a major virulence factor that acts as a global inhibitor of host cell transcription and antagonist of the IFN system (20-22), our previous studies have shown that, unlike any other bunyavirus NSs, the SFTS virus NSs interacts with and relocalizes TBK1, RIG-I, and TRIM25 into endosome-like structures (18). Thus, SFTS virus appears to use a different mechanism for virus replication and inhibition of IFN responses than those described for other bunyaviruses.